Is F5 p.Ser1148Pro (c.3442T>C) pathogenic?

F5 p.Ser1148Pro (c.3442T>C) is classified Conflicting classifications of pathogenicity in F5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-31). AlphaMissense: likely benign (0.082); Ultra-rare (popmax 0.0288%, nfe); Associated with Budd-Chiari syndrome.

What condition is associated with F5 p.Ser1148Pro (c.3442T>C)?

F5 p.Ser1148Pro (c.3442T>C) is associated with Budd-Chiari syndrome, thrombophilia due to thrombin defect, thrombophilia due to activated protein C resistance (ClinVar).

How common is F5 p.Ser1148Pro (c.3442T>C) in the general population?

F5 p.Ser1148Pro (c.3442T>C) is ultra-rare (popmax 0.0288%, nfe) (gnomAD).

How is Budd-Chiari syndrome inherited?

Typically Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about F5 p.Ser1148Pro (c.3442T>C)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

F5 p.Ser1148Pro

c.3442T>C · rs369276714 · VCV293607

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0288%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Budd-Chiari syndrome

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -6.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.44	GERP -2.5
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	5.723	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0288% European (non-Finnish) · 340/1,179,992 alleles

Filtering AF 0.0263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0253%

Overall 0.0217% 350/1,613,982 alleles · ultra-rare exomes 342/1,461,820 · genomes 8/152,162 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0288%	3,471
African / African-American	0.00801%	12,487
Remaining individualsnot grpmax-eligible	0.0064%	15,621

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: F5
Protein: p.Ser1148Pro
Coding: c.3442T>C
MANE Select: NM_000130
dbSNP: rs369276714
Type: single nucleotide variant
Location: chr1:169541648 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 1148: the 'b' region; the 'disordered' region

Full F5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Budd-Chiari syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to thrombin defect thrombophilia due to activated protein C resistance congenital factor V deficiency pregnancy loss, recurrent, susceptibility to, 1 factor V deficiency ischemic stroke

For Budd-Chiari syndrome (Orphanet):

Inheritance: Multigenic/multifactorial
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

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Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/f5-p-ser1148pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown